Sarah Queller

Neurocognitive Signs in Prodromal Huntington Disease

OBJECTIVE PREDICT-HD is a large-scale international study of people with the Huntington disease (HD) CAG-repeat expansion who are not yet diagnosed with HD. The objective of this study was to determine the stage in the HD prodrome at which cognitive differences from CAG-normal controls can be reliably detected. METHOD For each of 738 HD CAG-expanded participants, we computed estimated years to clinical diagnosis and probability of diagnosis in 5 years based on age and CAG-repeat expansion number (Langbehn, Brinkman, Falush, Paulsen, & Hayden, 2004). We then stratified the sample into groups: NEAR, estimated to be ≤9 years; MID, between 9 and 15 years; and FAR, ≥15 years. The control sample included 168 CAG-normal participants. Nineteen cognitive tasks were used to assess attention, working memory, psychomotor functions, episodic memory, language, recognition of facial emotion, sensory-perceptual functions, and executive functions. RESULTS Compared with the controls, the NEAR group showed significantly poorer performance on nearly all of the cognitive tests and the MID group on about half of the cognitive tests (p = .05, Cohens d NEAR as large as -1.17, MID as large as -0.61). One test even revealed significantly poorer performance in the FAR group (Cohens d = -0.26). Individual tasks accounted for 0.2% to 9.7% of the variance in estimated proximity to diagnosis. Overall, the cognitive battery accounted for 34% of the variance; in comparison, the Unified Huntingtons Disease Rating Scale motor score accounted for 11.7%. CONCLUSIONS Neurocognitive tests are robust clinical indicators of the disease process prior to reaching criteria for motor diagnosis of HD.

Motor abnormalities in premanifest persons with Huntington's disease: the PREDICT-HD study.

The PREDICT‐HD study seeks to identify clinical and biological markers of Huntingtons disease in premanifest individuals who have undergone predictive genetic testing. We compared baseline motor data between gene‐expansion carriers (cases) and nongene‐expansion carriers (controls) using t‐tests and Chi‐square. Cases were categorized as near, mid, or far from diagnosis using a CAG‐based formula. Striatal volumes were calculated using volumetric magnetic resonance imaging measurements. Multiple linear regression associated total motor score, motor domains, and individual motor items with estimated diagnosis and striatal volumes. Elevated total motor scores at baseline were associated with higher genetic probability of disease diagnosis in the near future (partial R2 0.14, P < 0.0001) and smaller striatal volumes (partial R2 0.15, P < 0.0001). Nearly all motor domain scores showed greater abnormality with increasing proximity to diagnosis, although bradykinesia and chorea were most highly associated with diagnostic immediacy. Among individual motor items, worse scores on finger tapping, tandem gait, Luria, saccade initiation, and chorea show unique association with diagnosis probability. Even in this premanifest population, subtle motor abnormalities were associated with a higher probability of disease diagnosis and smaller striatal volumes. Longitudinal assessment will help inform whether motor items will be useful measures in preventive clinical trials.

Mild cognitive impairment in prediagnosed Huntington disease

Background: Cognitive decline has been reported in Huntington disease (HD), as well as in the period before diagnosis of motor symptoms (i.e., pre-HD). However, the severity, frequency, and characterization of cognitive difficulties have not been well-described. Applying similar cutoffs to those used in mild cognitive impairment (MCI) research, the current study examined the rates of subtle cognitive dysfunction (e.g., dysfunction that does not meet criteria for dementia) in pre-HD. Methods: Using baseline data from 160 non–gene-expanded comparison participants, normative data were established for cognitive tests of episodic memory, processing speed, executive functioning, and visuospatial perception. Cutoff scores at 1.5 standard deviations below the mean of the comparison group were then applied to 575 gene-expanded pre-HD participants from the observational study, PREDICT-HD, who were stratified by motor signs and genetic risk for HD. Results: Nearly 40% of pre-HD individuals met criteria for MCI, and individuals closer to HD diagnosis had higher rates of MCI. Nonamnestic MCI was more common than amnestic MCI. Single-domain MCI was more common than multiple-domain MCI. Within the nonamnestic single-domain subtype, impairments in processing speed were most frequent. Conclusions: Consistent with the Alzheimer disease literature, MCI as a prodromal period is a valid concept in pre-HD, with nearly 40% of individuals showing this level of impairment before diagnosis. Future studies should examine the utility of MCI as a marker of cognitive decline in pre-HD.

Evaluation of longitudinal 12 and 24 month cognitive outcomes in premanifest and early Huntington's disease

Background Deterioration of cognitive functioning is a debilitating symptom in many neurodegenerative diseases, such as Huntingtons disease (HD). To date, there are no effective treatments for the cognitive problems associated with HD. Cognitive assessment outcomes will have a central role in the efforts to develop treatments to delay onset or slow the progression of the disease. The TRACK-HD study was designed to build a rational basis for the selection of cognitive outcomes for HD clinical trials. Methods There were a total of 349 participants, including controls (n=116), premanifest HD (n=117) and early HD (n=116). A standardised cognitive assessment battery (including nine cognitive tests comprising 12 outcome measures) was administered at baseline, and at 12 and 24 months, and consisted of a combination of paper and pencil and computerised tasks selected to be sensitive to cortical-striatal damage or HD. Each cognitive outcome was analysed separately using a generalised least squares regression model. Results are expressed as effect sizes to permit comparisons between tasks. Results 10 of the 12 cognitive outcomes showed evidence of deterioration in the early HD group, relative to controls, over 24 months, with greatest sensitivity in Symbol Digit, Circle Tracing direct and indirect, and Stroop word reading. In contrast, there was very little evidence of deterioration in the premanifest HD group relative to controls. Conclusions The findings describe tests that are sensitive to longitudinal cognitive change in HD and elucidate important considerations for selecting cognitive outcomes for clinical trials of compounds aimed at ameliorating cognitive decline in HD.

Motivational processes and autonomic responsivity in Asperger's disorder: evidence from the Iowa Gambling Task.

Aspergers disorder (ASP), like other autism spectrum disorders, is associated with altered responsiveness to social stimuli. This study investigated learning and responsiveness to nonsocial, but motivational, stimuli in ASP. We examined choice behavior and galvanic skin conductance responses (SCRs) during the Iowa Gambling Task (IGT; Bechara et al., 1994) in 15 adolescents and young adults with ASP and 14 comparison subjects. We examined aspects of learning, attention to wins and losses, and response style with a formal cognitive model, the Expectancy-Valence Learning model (Busemeyer & Stout, 2002). The ASP group did not differ from the comparison group in proportions of selections from advantageous decks. However, ASP participants showed a distinct pattern of selection characterized by frequent shifts between the four IGT decks, whereas comparison participants developed clear deck preferences. SCR results showed some evidence of reduced responsiveness in the ASP group during the IGT. Results from the cognitive model indicated that, in contrast to the comparison group, the ASP groups selections were less consistent with the motivational significance they assigned to decks. Findings are discussed in the context of the neurobiological substrates associated with IGT performance.

Ten-year rate of longitudinal change in neurocognitive and motor function in prediagnosis Huntington disease†

Longitudinal studies of neurocognitive function in prediagnosis Huntington disease (pre‐HD) have been few, and duration of follow‐up has been brief. In this study, 155 individuals at‐risk for HD completed a battery of cognitive and motor tasks at two study visits ∼10 years apart. Participants were classified as: (1) at‐risk, without the CAG expansion (healthy controls, NC; n = 112), or (2) CAG expanded (CAG+; n = 43). To examine the rate of decline at different stages of the pre‐HD period, participants in the CAG+ group were further characterized as converters (i.e., individuals who developed manifest HD over the course of the study; n = 21) or nonconverters (n = 22), and their performances were compared. The CAG+ group exhibited faster rates of neurocognitive decline over the course of the study, relative to the NC group. In addition, more rapid decline was associated with closer proximity to estimated age of disease onset in the CAG+ group. Faster rates of motor and psychomotor decline were observed in the CAG+ converter group, relative to the nonconverters. These findings suggest that neurocognitive decline in pre‐HD, particularly in motor and psychomotor domains, begins insidiously and accelerates as individuals approach disease onset.

HD-CAB: A cognitive assessment battery for clinical trials in Huntington's disease

Cognitive dysfunction is central to Huntingtons disease (HD) and undermines quality of life. Clinical trials are now targeting cognitive outcomes in HD; however, no cognitive battery has been optimized for HD clinical trials. We evaluated 16 cognitive tests in a 20‐site, five‐country, observational study designed to mimic aspects of a clinical trial (e.g., data collection managed by a contract research organization, repeated testing, prespecified statistical analyses). Fifty‐five early HD, 103 premanifest HD (pre‐HD), and 105 controls were tested at visit 1, visit 2 (1‐3 days later), and visit 3 (5‐7 weeks after visit 1). For inclusion in a recommended battery, tests were evaluated for sensitivity, practice effects, reliability, domain coverage, feasibility, and tolerability. Most tests differentiated controls from pre‐HD and early HD and showed excellent psychometric properties. We selected six tests to constitute the Huntingtons Disease Cognitive Assessment Battery (HD‐CAB): Symbol Digit Modalities Test, Paced Tapping, One Touch Stockings of Cambridge (abbreviated), Emotion Recognition, Trail Making B, and the Hopkins Verbal Learning Test. These tests demonstrated sensitivity to disease status (Cohens d effect sizes: early HD= −1.38 to −1.90 and pre‐HD= −0.41 to −0.78), and acceptable reliability (rs 0.73‐0.93). A composite score yielded large effect sizes (early HD = −2.44 and pre‐HD = −0.87) and high reliability (r = 0.95). HD‐CAB is the first cognitive battery designed specifically for use in late premanifest and early HD clinical trials. Adoption of the HD‐CAB will facilitate evaluation of treatments to improve cognition in HD.

Asymmetries in categorization, perceptual discrimination, and visual search for reference and nonreference exemplars.

In two experiments, we examined the representation, treatment, and attention devoted to the members of reference (i.e., club members) and nonreference (i.e., not club members) categories. Consistent with prior work on category interrelatedness (e.g., Goldstone, 1996 ; Goldstone, Steyvers, & Rogosky, 2003), the findings reveal the existence of asymmetric representations for reference and nonreference categories, which, however, decreased as expertise and familiarity with the categories increased (Experiments 1 and 2). Participants also more readily judged two reference exemplars as being the same than they did two nonreference exemplars (Experiment 1) and were better at detecting reference than nonreference exemplars in a set of novel, category-unspecified exemplars (Experiment 2). These findings provide evidence for the existence of a feature asymmetry in the representation and treatment of exemplars from reference and nonreference categories. Membership in a reference category acts as a salient feature, thereby increasing the perceived similarity and detection of faces that belong in the reference, in comparison with the nonreference, category.

Are cognitive changes progressive in prediagnostic HD

ObjectiveTo characterize neurocognitive signs of disease progression in prediagnosis and early Huntington disease (HD) and compare the sensitivity of 2 disease staging classification schemes for detecting these signs. MethodsThree hundred and six individuals at-risk for or recently diagnosed with HD completed the Unified Huntingtons Disease Rating Scale, genetic testing, and a neurocognitive battery. Two schemes were used to estimate latency to onset of disease. One was based on genetic information (CAG repeat length) and the other was based on the extent of motor signs. Effect sizes were compared to assess the relative sensitivity of the 2 schemes for detecting signs of disease progression. ResultsCAG-expanded participants far from estimated diagnosis performed similarly to controls, whereas those near to estimated diagnosis were impaired relative to controls. Overall, the method employing genetic information yielded larger effect sizes than the motor scheme, particularly for strategic and executive function measures; the motor scheme resulted in a larger effect size for a measure of motor/psychomotor function. ConclusionsNeurocognitive function is not uniformly affected in prediagnosis and early HD; individuals near to their estimated age of diagnosis have cognitive signs similar to HD, whereas individuals far from estimated diagnosis appear cognitively normal. Classification schemes that incorporate both genetic and phenotypic information may be more sensitive for tracking neurocognitive signs of disease progression.

A novel view of between-categories contrast and within-category assimilation

This research manipulated the portion of a category distribution that is misclassified by the optimal classifier and investigated the impact on assessments of category attributes. Three separate studies manipulated the direction of overlap, the extent of overlap, and the relative base rate of the comparison category. All 3 studies produced large between-categories contrast and within-category assimilation. As expected, these effects were enhanced in conditions in which the optimal classifier misclassified a larger portion of the target category. Study 4 demonstrated that intercategory overlap in the absence of overt classification does not produce contrast and assimilation. Ironically, optimizing categorization accuracy can produce highly inaccurate beliefs about category attributes.